Glucose Metabolism

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Page Contents

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Definitions
Physiology: Carbohydrates
Physiology: Carbohydrate Metabolism
Pathophysiology: Lactic Acid
Pathophysiology: Insulin
Pathophysiology: Type I Diabetes
Pathophysiology: Type II Diabetes Mellitus
References
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II. Definitions

Carbohydrates
1. Largest class of organic compounds, and contain 3 or more carbons and multiple hydroxyl groups (OH)
2. Include starches (Glucose polymers, e.g. glycogen), Disaccharides (e.g. sucrose) and Monosaccharides (e.g. Glucose)
3. Most Carbohydrates also contain either an aldehyde group (as with Glucose) or keto group (as with fructose)
4. Functions include energy sources, cell signaling, structural molecules and synthesis of Amino Acid, Nucleic Acid, lipid
Glycolysis (Embden-Meyerhoff Pathway, Glycolytic Pathway)
3. Catabolic pathway to breakdown Carbohydrates (Glucose, fructose) into pyruvate, without need for oxygen
4. Represents only a small part of the overall energy generation from Carbohydrates (2 net ATP and 1 NADH)
5. Pyruvate may then be converted to acetyl-CoA (or, when oxygen is unavailable to Lactic Acid)
  1. Acetyl CoA enters TCA Cycle for energy generation (or is used to form Triglycerides)
6. Triggered by Insulin, which lowers Glucose via both Glycolysis as well as increasing glycogen stores
7. Glycolysis occurs in the cytoplasm of cells throughout the body
Acetyl Coenzyme A (Acetyl CoA)
1. Synthesized from Coenzyme A and acetic acid
2. Acetyl CoA is substrate in the biosynthesis of Fatty Acids, sterols and Amino Acids
3. Serves as entry point of Citric Acid Cycle
  1. Feeds it substrate from Glucose (and other Carbohydrate), Amino Acid and Fatty Acid catabolism
Citric Acid Cycle (Krebs Cycle, Tricarboxylic Acid Cycle, TCA Cycle)
3. Universal pathway seen across multicellular organisms, taking place in the mitochondria of humans
  1. Citric Acid Cycle does not occur in Red Blood Cells (which lack mitochondria)
4. Generates energy from Acetyl CoA (3 NADH, 1 FADH, 1 GTP) derived primarily from Glucose
5. Intermediate steps include oxaloacetate, isocitrate, a-Ketoglutarate, succinyl-CoA, Succinate, fumarate, malate
  1. Kreb Cycle intermediates also lead to other pathways (e.g. succinyl-CoA to heme synthesis pathways)
6. With decreased Energy Intake or increased Energy Expenditure, Glucose reserves (e.g. glycogen) are exhausted
  1. In early starvation, Fatty Acids are catabolized to acetyl CoA (and Glycerol), fueling the Krebs Cycle
  2. With longer starvation, Amino Acids are catabolized to enter the Krebs Cycle
Gluconeogenesis
2. Pathway forms Glucose from 3- or 4-carbon noncarbohydrate precursors (e.g. pyruvate, Amino Acids and Glycerol)
3. Process takes place in the liver (and Kidney) and is triggered when Insulin levels are low and in starvation states
4. The same triggers for Gluconeogenesis also trigger Lipolysis and Ketogenesis
5. 3 enzymes limit Gluconeogenesis to liver (Pyruvate carboxylase, Fructose Diphosphatase, Glucose 6-Phosphatase)
Hexose Monophosphate Shunt (HMP Shunt, Pentose Shunt, Pentose Phosphate Path, Phosphogluconate Oxidative Pathway)
1. Glucose-6P is converted to a 5 carbon sugar, Ribose-5P, over several steps that generate two NADPH and CO2
2. NADPH is a Reducing Agent (donating H+) in cellular reactions
  1. Active throughout the body (including in RBCs, which lack mitochondria)
3. Ribose-5P is used to generate Nucleic Acids (DNA, RNA)
  1. When Ribose-5P is in excess, it may be converted to Glyceradehyde-3P (Glycolytic Pathway)
Glucuronidation
1. Glucuronic Acid (UDP-Glucuronate) is a water soluble derivative of Glucose, synthesized in the liver
2. In Glucuronidation, Glucuronic acid is conjugated to other molecules to facilitate their excretion in urine and bile
3. Glucuronidation inactivates and detoxifies various substances (e.g. Bilirubin, bile acids, sex Hormones, Corticosteroids)

III. Physiology: Carbohydrates

Carbohydrates, when burned as energy, generate 4 Kcals/g, and are exhausted in first day of starvation
Starches and Disaccharides are cleaved into Monosaccharides before intestinal absorption
1. Mediated by Stomach acid and Salivary, intestinal and Pancreatic Enzymes (see below)
2. Amylase (Saliva, Pancreas) cleaves starches into Glucose and Disaccharides in the Gastrointestinal Tract
3. Intestinal wall enzymes cleave Disaccharides: sucrose (sucrase), lactose (lactase) and maltose (maltase)
4. Simple Sugars (Glucose, fructose and galactose) are absorbed across the small intestinal epithelial cell walls
Polysaccharides
1. Combination of more than 10 Monosaccharides (Simple Sugars)
2. Branched structures (glycogen, amylopectin) allow for efficient building and breakdown of chains
  1. Multiple end points allows for multiple reactions to occur in parallel, simultaneously
3. Starches (Glucose polymers, cleaved by amylase into maltose)
  1. Amylose
    1. Unbranched chain of Glucose molecules linked by alpha 1,4
  2. Amylopectin
    1. Branched Glucose chains with the addition of alpha 1,6 links
  3. Glycogen
    1. Highly branched chains of Glucose molecules
    2. Key Glucose storage overall in humans
4. Structural Polysaccharides
  1. Cellulose
    1. Polymer of Glucose molecules chained by beta-links
    2. Unlike the alpha-linked starches, humans cannot cleave beta-linked Glucose
      1. Cellulose is therefore passed in human stool without absorption
      2. Contrast with other animals able to digest cellulose (e.g. cows, termites)
  2. Chitin
    1. Forms the cell wall of fungi, and the exoskeleton of arthropods
  3. Pectin
    1. Alpha1,4 linked galacturonic acid polymer found in non-woody cell plant cell walls
    2. Extracted from citrus fruits, and used as a gelling agent in cooking (e.g. jams)
Oligosaccharides
1. Combination of 3 to 10 Monosaccharides (Simple Sugars)
2. Function in cell signaling, cell adhesion and cell recognition
3. Dietary Oligosaccharides
  1. Fructo-Oligosaccharides (chain of fructose molecules, e.g. found in vegetables)
  2. Galacto-Oligosaccharides (chain of galactose molecules, e.g. found in milk)
4. Often a part of glycans, Glycoproteins (linked to Amino Acids) or Glycolipids (linked to lipids)
  1. See Glycolipids
  2. N-Linked Oligosaccharides (attached to Asparagine)
  3. O-Linked Oligosaccharides (linked to Threonine or Serine)
  4. Glycoprotein
    1. Synthesis
      1. Fructose 6-P joins Glutamine to form Glucosamine 6-P (amino sugar)
      2. Glucosamine 6-P may be transformed into other amino sugars
      3. Amino sugars are joined with simple Carbohydrates
    2. Functions
      1. Glycolipid components
        N-Acetyl Galactosamine (8 carbon amino sugar)
        Sialic Acids (11 carbon amino sugars)
      2. Cell membrane components
        Antigenic sites (including ABO Blood Type)
        Receptor sites
      3. Blood Proteins
        Some Hormones (e.g. TSH, FSH)
        Immunoglobulins
        Blood Clotting Proteins
      4. Proteoglycans
        Contain glycosaminoglycans or mucopolysaccharides (predominant Carbohydrate components)
        Glycosaminoglycans are viscous or mucoid (high water consistency)
        Examples include hyaluronic acid, chondroitan sulfate, Heparin
Disaccharides
1. Combination of two Monosaccharides (Simple Sugars)
2. Sucrose (Glucose+fructose, cleaved by sucrase)
3. Lactose (Glucose+galactose, cleaved by lactase)
4. Maltose (Glucose+Glucose, cleaved by maltase)
Monosaccharides (Simple Sugars)
1. Monosaccharides are Carbohydrates that cannot be hydrolyzed (lysed with water) to simpler sugars
  1. Trioses have 3 carbons
  2. Tetroses have 4 carbons
  3. Pentoses have 5 carbons
  4. Hexoses have 6 carbons
2. Hexose Examples
  1. Glucose
    1. Glucose is the primary cellular fuel stored in glycogen or metabolized via Glycolysis
    2. Blood Glucose increases via intestinal absorption, gluoconeogenesis or glycogenolysis
  2. Fructose
    1. Absorbed from the intestinal tract after sucrose is cleaved into Glucose and fructose
    2. Fructose may be metabolized to a 3 carbon sugar that enters the Glycolysis pathway
    3. Also used to generate lipids (via fructose 1P, glyceraldehyde 3P, dihydroxyacetone P)
  3. Galactose
    1. Absorbed from the intestinal tract after lactose is cleaved into Glucose and galactose
    2. Galactose may be converted to Glucose-UDP and then metabolized or stored as Glucose
    3. Important role in glycans, Glycoproteins (linked to Amino Acids) or Glycolipids (linked to lipids)

IV. Physiology: Carbohydrate Metabolism

See Gastrointestinal Metabolism
Images
Glycogen Storage
1. Excess Blood Glucose is stored in glycogen
  1. Glucose is converted to Glucose 6P, Glucose 1P and then UDP Glucose
  2. UDP Glucose is then linked into amylose (non-branched) and finally glycogen (branched)
2. Glycogen breakdown occurs when Blood Glucose levels are falling
  1. Glycogen is branched (1-6 bond) and requires a debranching enzyme during breakdown
  2. Phosphorylase cleaves off Glucose from non-branched Glucose chains into Glucose-1P
    1. Phosphorylase stops cleaving Glucose as it approaches 1-6 branches
    2. Debranching must occur next before Phosphorylase continues on the current chain
    3. In Muscle, Glucose-1P (and Glucose-6P) is trapped within the cell and utilized for Muscle energy
    4. In liver, Glucose-1P is converted to Glucose-6P, then via Glucose 6-Phosphatase to Glucose
      1. Glucose exits the liver cells, and is used systemically by cells for energy
  3. Other methods of direct glycogen breakdown
    1. Alpha-Glucosidase within Lysosomes breaks down glycogen directly to Glucose
    2. Amylase (Pancreas, Salivary Glands)
      1. Breaks down starches to maltose, which in turn is cleaved into Glucose
      2. Glucose is readily absorbed across the intestinal lining
  4. Glycogen breakdown is stimulated by Epinephrine (Muscle Cells) and Glucagon (liver cells)
    1. Both Epinephrine and Glucagon act at the cell membrane to stimulate adenylate cyclase
    2. Triggers cyclic AMP which in turn activates phosphorylase and glycogen breakdown
Blood Glucose
1. Released from hepatic stores between meals
2. Derived from ingested Carbohydrates
  1. Postprandial Glucose >20 fold over hepatic release
Insulin
1. See Insulin
2. General
  1. Insulin is an anabolic Hormone that is released in the fed state
    1. Involves triggers mechanisms to move Blood Glucose into storage
    2. Insulin is produced by pancreatic beta cells
    3. Insulin release is stimulated by Blood Glucose
  2. Insulin response to Glucose is linear
    1. Insulin response is based on Glucose sensitivity
    2. Glucose sensitivity depends on Ambient Glucose
      1. Normal: Rapid Insulin release with a meal
      2. Fasting: Steeper rate of Insulin release
      3. Prolonged Hyperglycemia: Flattened response
  3. Overall Insulin effects
    1. Promotes Glucose uptake by liver and Muscle and for storage as glycogen
      1. Does not effect brain Glucose uptake (Glucose freely crosses blood brain barrier)
    2. Promotes cellular uptake of Amino Acids and Protein synthesis
    3. Promotes hepatic synthesis of Fatty Acids, VLDL transport to adipose for Triglyceride storage
    4. Promotes Glycolysis for energy utilization
    5. Suppresses Gluconeogenesis
3. Phase 1 Insulin Release
  1. Duration: 10 minutes
  2. Suppresses hepatic Glucose release
4. Phase 2 Insulin Release
  1. Duration: 2 hours
  2. Controls mealtime Carbohydrates
5. Basal insulin Release
  1. Low continuous Insulin level
  2. Covers metabolic needs between meals
Glucagon
1. See Glucagon
2. Endogenous polypeptide Hormone secreted by pancreatic alpha cells
3. Opposite effect of Insulin
  1. While Insulin lowers Serum Glucose (glycogen storage, Glycolysis), Glucagon increases Serum Glucose
  2. However, both Insulin and Glucagon increase Amino Acid uptake from the liver
4. Hypoglycemia effect (primary)
  1. Hypoglycemia Increases pancreatic secretion of Glucagon
  2. Glucagon stimulates Glucose release from glycogen (glycogenolysis)
  3. Glucagon also stimulates Glucose synthesis (Gluconeogenesis)
5. Inhibitors of Glucagon release
  1. Hyperglycemia
    1. Inhibits pancreatic secretion of Glucagon
  2. GLP1 (Incretin)
    1. Secreted by Small Bowel
    2. Stimulates pancreatic beta cells and inhibits Glucagon
    3. See Incretin Mimetics (used in Type 2 Diabetes Mellitus)
6. Amino Acid Excess Effect
  1. Increases pancreatic secretion of Glucagon
  2. Glucagon stimulates liver uptake of Amino Acids
    1. Both Insulin and Glucagon increase liver uptake of Amino Acids
7. Glucagon has similar activity to Epinephrine (in terms of Glucose Metabolism)
  1. Most active in liver (contrast with Epinephrine which is most active in Muscle)
  2. Both Epinephrine and Glucagon act at the cell membrane to stimulate adenylate cyclase
    1. Triggers cyclic AMP which in turn activates phosphorylase and glycogen breakdown
  3. Glucagon also acts at Catecholamine-independent receptors on cardiac cells
    1. Increases intracellular Calcium in cardiac cells
    2. Increases myocardial contractions
Epinephrine
1. See Epinephrine
2. Epinephrine has alpha-adrenergic effects (esp. alpha-2) specific to metabolism
  1. Increases Serum Glucose (Gluconeogenesis, Glycogenolysis)
  2. Increases Fatty Acids (Fat cell lipolysis of Triglycerides)
  3. Similar activity to Glucagon (in terms of Glucose Metabolism)
    1. Most active in Muscle (contrast with Glucagon which is most active in the liver)
  4. Both Epinephrine and Glucagon act at the cell membrane to stimulate adenylate cyclase
    1. Triggers cyclic AMP which in turn activates phosphorylase and glycogen breakdown
3. Most of Epinephrine's primary effects are cardiopulmonary
  1. Alpha Adrenergic Agonist Effects
    1. Vasoconstriction (increased Systemic Vascular Resistance and Blood Pressure)
    2. Increases Vital Organ Perfusion (myocardial and cerebral perfusion)
    3. Decreases Non-Vital Organ Perfusion
      1. Decreases splanchnic and intestinal perfusion
      2. Decreases renal and skin perfusion
  2. Beta Adrenergic Agonist effects (Under 0.3 ug/kg/min)
    1. Increases myocardial contractility and Heart Rate
    2. Relaxes Bronchial Smooth Muscle (bronchodilation)
Growth Hormone
1. See Growth Hormone
2. Polypeptide produced in the acidophil cells of the anterior pituitary
3. Hypothalamus controls release when triggered by Hypoglycemia, decreased Amino Acids
  1. Growth Hormone Releasing Hormone (GHRH) stimulates release
  2. Somatostatin inhibits release
4. Biochemistry
  1. Liver converts Growth Hormone to Insulin-like growth factor (IGF-1) and stimulates other growth factors
  2. Growth Hormone is a precursor to Testosterone
5. Positive Function (stimulates or promotes the following activities)
  1. Bone and cartilage growth
  2. Protein synthesis
  3. Promotes Fatty Acid use as fuel instead of Glucose
    1. Lipid catabolism to Fatty Acids (for energy source)
    2. Hyperglycemia (from decreased cell utilization of Glucose) resulting in an increase of glycogen stores
Cortisol
1. See Cortisol
2. Cortisol is synthesized in the Adrenal Cortex, derived from Cholesterol (See Cortisol Synthesis_
3. Cortisol secretion is stimulated by Adrenocorticotropic Hormone (ACTH) in response to stress (See Pituitary Gland)
4. Cortisol functionality
  1. Mobilizes available energy sources (Glucose, fats, Amino Acids)
    1. Increases Serum Glucose by stimulating liver Gluconeogenesis and glycogenolysis
    2. Increases serum Fatty Acids by promoting lipolysis of adipose Triglyceride stores
    3. Increases blood Amino Acids by breaking down Proteins (outside liver)
      1. Within liver, Cortisol induces Protein synthesis
  2. Antiinflammatory activity
    1. Inhibit Histamine release
    2. Inhibit Lymphocyte production
    3. Stabilize Macrophage Lysosomes
  3. Increases gastric acid production
Incretin
1. Group of peptides
  1. Glucagon-Like Peptide-1 (GLP-1)
  2. Glucose Dependent Insulinotropic Peptide (GIP) or Gastric inhibitory peptide
2. Functions
  1. Triggers Insulin synthesis
  2. Inhibit Glucagon secretion
  3. Decreases gastric emptying

V. Pathophysiology: Lactic Acid

See Lactic Acid
Lactic Acid is generated when oxygen is unavailable to allow for Krebs Cycle related Oxidative Phosphorylation
1. Occurs with both skeletal Muscle anaerobic metabolism as well as other physiologic stress (e.g. Sepsis)
2. Lactic Acid may also be generated during aerobic conditions
Glycolysis generates 7 net ATP/Glucose (compared with 25 for Kreb Cycle) and does not require oxygen
However, Glycolysis does use NAD+ (for glyceraldehyde 3-P to 1,3P2-glycerate)
2. NAD+ is typically replenished in the Krebs Cycle related Oxidative Phosphorylation
3. When oxygen is unavailable, pyruvate is metabolized to Lactic Acid, regenerating NAD+
Lactic Acid conversion back to Glucose (Gluconeogenesis) requires several additional steps
2. Muscle Cells release generated Lactic Acid
3. Lactate may be directly utilized by the Heart (up to 60% of energy demands) and brain (up to 25% of energy demands)
4. Lactic Acid is transported via systemic circulation to liver and Kidney
  1. Liver (70-75%) and Kidney (25-30%) cells perform lactate metabolism (Gluconeogenesis)
  2. Three Enzymes required for Gluconeogenesis from Lactic Acid are only in cells of the liver and Kidney
    1. Pyruvate carboxylase
    2. Fructose Diphosphatase
    3. Glucose 6-Phosphatase

VI. Pathophysiology: Insulin

Insulin excess
1. See Hypoglcemia
2. See Insulin Shock (Insulin Overdose, Insulin Reaction)
Insulin at low levels or deficiency
1. Causes
  1. Low Insulin due to Diabetes Mellitus
    1. In Type I Diabetes, Insulin deficiency is key
    2. In Type II Diabetes, Insulin Resistance is key initially, but later Insulin deficiency results
  2. Low Insulin as a normal physiologic response to Hypoglycemia
2. Low Insulin effects
  1. Gluconeogenesis and Glycogenolysis results in Hyperglycemia
  2. Lipolysis (Triglyceride breakdown to Fatty Acids)
    1. Further lysed into acetyl coA to be utilized in the Kreb Cycle (TCA Cycle, Citric Acid Cycle)
    2. Other Fatty Acids are diverted to Ketogenesis (Ketone formation)
      1. Occurs in Diabetic Ketoacidosis, Starvation Ketosis, Alcoholic Ketoacidosis
    3. Fatty Acids also form excess Cholesterol, Triglycerides within VLDL with increasing atherosclerosis

VII. Pathophysiology: Type I Diabetes

See Type I Diabetes Mellitus
See Maturity Onset Diabetes of the Young
Deficiency of Insulin, with multiple underlying mechanisms
Type 1A
1. Environmental and genetic factors
2. HLA-DR4 association
3. Cell mediated pancreatic beta cell destruction
Type 1B (uncommon)
1. Primary Autoimmune Condition
2. Associated with other Autoimmune Conditions
3. HLA-DR3 association
4. Incidence highest in 30-50 year olds
Secondary Diabetes Mellitus
1. Cystic Fibrosis

VIII. Pathophysiology: Type II Diabetes Mellitus

See Type II Diabetes Mellitus
Loss of Glucose sensitivity (see above)
1. Loss of phase 1 Insulin response
2. Insufficient phase 2 Insulin response
Insulin production by beta cell
1. First: Insulin increases to overcome Glucose toxicity
2. Results in beta-cell exhaustion (Glucose Toxicity)
  1. Initially reversible beta cell exhaustion
  2. Permanent later as amyloid replaces beta cells
3. Insulin levels decrease as beta cells fail
  1. Beta-cell function reduced to <50% by DM diagnosis
Impaired Incretin action
1. Incretins manage postprandial Glucose levels
  1. Incretin released from GI Tract following meals
2. Endogenous Incretin effects
  1. Increases Glucose dependent Insulin secretion
  2. Delays gastric emptying
  3. Decreases food intake (improves satiety)
3. Progressive Incretin reduced activity
  1. Glucagon-Like Peptide 1 (GLP-1) activity decreases
Medications
1. Increase Insulin sensitivity
  1. Metformin
  2. Thiazolidinediones
2. Stimulate Insulin release from beta cells
  1. Meglitinides (act on phase 1 release)
  2. Sulfonylureas (act on phase 2 release)
3. Replace Insulin
  1. See Insulin
4. Increase Incretin levels (GLP-1)
  1. Exenatide (Byetta)
  2. Sitagliptin (Januvia)

IX. References

Goldberg (2014) Clinical Physiology, Medmasters, Miami, p. 120-46
Goldberg (2001) Clinical Biochemistry, Medmasters, Miami, p. 13-16
Guyton and Hall (2006) Medical Physiology, 7th Ed, Elsevier Saunders, Philadelphia, p. 829-58

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